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Nat Med. 2015 May;21(5):512-7. doi: 10.1038/nm.3828. Epub 2015 Apr 20.

Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion.

Author information

1
1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Centre Hospitalier Régional Universitaire, Lille, France.
2
1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Centre Hospitalier Régional Universitaire, Lille, France. [4] Université de Lille, Lille, France.
3
1] European Genomic Institute for Diabetes, Lille, France. [2] INSERM UMR 1190, Lille, France. [3] Université de Lille, Lille, France.
4
Laboratory of Experimental Hormonology, Medical School, Université Libre de Bruxelles, Brussels, Belgium.
5
1] Université de Lille, Lille, France. [2] INSERM UMR 1177, Lille, France. [3] Institut Pasteur de Lille, Lille, France.
6
1] European Genomic Institute for Diabetes, Lille, France. [2] Université de Lille, Lille, France. [3] CNRS UMR 8199, Lille, France.
7
1] European Genomic Institute for Diabetes, Lille, France. [2] Université de Lille, Lille, France. [3] Institut Pasteur de Lille, Lille, France. [4] INSERM UMR 1011, Lille, France.

Abstract

Type 2 diabetes (T2D) is characterized by chronic hyperglycemia resulting from a deficiency in insulin signaling, because of insulin resistance and/or defects in insulin secretion; it is also associated with increases in glucagon and endogenous glucose production (EGP). Gliflozins, including dapagliflozin, are a new class of approved oral antidiabetic agents that specifically inhibit sodium-glucose co-transporter 2 (SGLT2) function in the kidney, thus preventing renal glucose reabsorption and increasing glycosuria in diabetic individuals while reducing hyperglycemia. However, gliflozin treatment in subjects with T2D increases both plasma glucagon and EGP by unknown mechanisms. In spite of the rise in EGP, T2D patients treated with gliflozin have lower blood glucose levels than those receiving placebo, possibly because of increased glycosuria; however, the resulting increase in plasma glucagon levels represents a possible concerning side effect, especially in a patient population already affected by hyperglucagonemia. Here we demonstrate that SGLT2 is expressed in glucagon-secreting alpha cells of the pancreatic islets. We further found that expression of SLC5A2 (which encodes SGLT2) was lower and glucagon (GCG) gene expression was higher in islets from T2D individuals and in normal islets exposed to chronic hyperglycemia than in islets from non-diabetics. Moreover, hepatocyte nuclear factor 4-α (HNF4A) is specifically expressed in human alpha cells, in which it controls SLC5A2 expression, and its expression is downregulated by hyperglycemia. In addition, inhibition of either SLC5A2 via siRNA-induced gene silencing or SGLT2 via dapagliflozin treatment in human islets triggered glucagon secretion through KATP channel activation. Finally, we found that dapagliflozin treatment further promotes glucagon secretion and hepatic gluconeogenesis in healthy mice, thereby limiting the decrease of plasma glucose induced by fasting. Collectively, these results identify a heretofore unknown role of SGLT2 and designate dapagliflozin an alpha cell secretagogue.

PMID:
25894829
DOI:
10.1038/nm.3828
[Indexed for MEDLINE]
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